Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6

Abstract

1. This study aimed to characterise the pharmacokinetics of dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects.2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study.3. The geometric mean (per cent coefficient of variability) area under the concentration–time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 1662 ngċh/mL (26%) and 21.51 ng/mL (27%), respectively, for dacomitinib and 469 ngċh/mL (65%) and 5.54 ng/mL (79%) for PF-05199265. Median times to Cmax were 8 and 4 h postdose for dacomitinib and PF-05199265, respectively; mean terminal half-life of dacomitinib was 62.7 h. Geometric mean apparent clearance and volume of distribution of dacomitinib were 27.06 L/h and 2415 L, respectively. The metabolite PF-05199265-to-dacomitinib ratios were 0.2907 for AUCinf and 0.2656 for Cmax.4. Dacomitinib total (AUCinf) and peak exposures (Cmax) were similar among subjects with different CYP2D6 genotypes, whereas both parameters for PF-05199265 were higher in extensive metabolisers (n = 5) versus intermediate metabolisers (n = 8).